EP0173921B1 - Verfahren zur Racemisierung einer alpha-Aminocarbonsäure - Google Patents

Verfahren zur Racemisierung einer alpha-Aminocarbonsäure Download PDF

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Publication number
EP0173921B1
EP0173921B1 EP85110569A EP85110569A EP0173921B1 EP 0173921 B1 EP0173921 B1 EP 0173921B1 EP 85110569 A EP85110569 A EP 85110569A EP 85110569 A EP85110569 A EP 85110569A EP 0173921 B1 EP0173921 B1 EP 0173921B1
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EP
European Patent Office
Prior art keywords
acid
amino acid
dihydroxyphenylglycine
ketone
hydroxyphenylglycine
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Expired
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EP85110569A
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English (en)
French (fr)
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EP0173921A1 (de
Inventor
Victor Witold Jacewicz
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Beecham Group PLC
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Beecham Group PLC
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Priority to AT85110569T priority Critical patent/ATE34381T1/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B55/00—Racemisation; Complete or partial inversion
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds

Definitions

  • This invention relates to a chemical process for the racemisation of a-amino acids.
  • Optically active a-amino acids are useful in the synthesis of many physiologically active compounds, in particular as side-chains in penicillin and cephalorsporin antibiotics. It is convenient to synthesize a-amino acids in the racemic form and then resolve into the separate enantiomers. However, in most cases, only one enantiomer has commercial utility and it is therefore desirable to racemise the unwanted isomer, so that the racemate produced may again be subjected to resolution.
  • British Patent 1,432,822 describes the racemisation of an ester of an amino acid by the use of an aldehyde or ketone.
  • British Patent 1,417,060 describes the racemisation of an N-acyl amino acid by heating in a solvent selected from phosphoric acid tri-esters, lower fatty acids containing up to 4 carbon atoms, dialkylformamides, ketones and dialkylsulphoxides.
  • British Patent 1,560,907 describes the racemisation of an amide of an amino acid by heating in solvent in the presence of a ketone and an acid having a dissociation constant below 1.8x 10- 4 .
  • Japanese patent application 1512/78 (Kokai 54-109912) describes the racemisation of an ester of an amino acid by heating in the presence of a ketone and a protonic or Lewis acid.
  • European patent specification No. 57092 describes the racemisation of an amino acid itself or a salt thereof in the presence of an aliphatic acid and an aldehyde.
  • German patent 1 543 919 describes a process for the racemisation of an optically active amino acid by treatment with an a-ketocarboxylic acid and metal ions at 50-110°.
  • Japanese patent application (Kokai 52-71 440) describes a conventional resolution of DL-p-hydroxyphenylglycine by treatment with optically active bromocamphor sulphonic acid to give diastereoisomeric salts which are then separated by solubility differences.
  • the present invention relates to the racemisation of free amino acids by the use of a ketone in the presence of an organic acid.
  • the above prior art teaches away from such a process.
  • the present invention provides a process for racemisation of an a-amino acid or salt thereof which comprises treating an optically active a-amino acid of formula (I). wherein R represents phenyl optionally substituted with up to three groups selected from hydroxy or halogen, characterised in that the a-amino acid of formula I or salt thereof is treated with a ketone in the presence of an organic acid.
  • Suitable a-amino acids of formula (I) include phenylglycine, mono- and di-hydroxyphenyl glycines. Particularly preferred a-amino acids of formula (I) are 4-hydroxyphenyl glycine and 3,4-dihydroxyphenylglycine.
  • the a-amino acid may be employed in the form of the acid itself or a salt thereof.
  • Suitable salts of the a-amino acid include acid salts, basic salts, internal zwitterionic salts and acid addition salts.
  • alkali metal salts such as sodium
  • acid addition salts such as acetate or benzoate.
  • salts which have been used in the resolution of the a-amino acid such as bromocamphor sulphonate salts.
  • Ketones which are suitable for the process of the invention may have the formula II: wherein R' and R 2 may be the same or different and each represents a hydrocarbon or heterocyclic group, as defined above, or R' and R 2 together complete a cycloalkanone ring.
  • ketones include acetone, methylethylketone, methylisobutylketone, cyclohexanone and cyclopetanone.
  • the ketone may be employed in excess. Conveniently the quantity of ketone employed is from 2% to 50% of the total solvent volume, i.e. 0.5 to 20 mole, preferably 1 to 10 mole per mole of a-amino acid.
  • Organic acids which are suitable for the process of the invention include C l - 6 alkanoic acids, for example formic acid, acetic acid, propionic acid and butyric acid.
  • a preferred organic acid is acetic acid. It is preferred to use from 5 to 50 moles of organic acid per mole of amino acid.
  • the organic acid, together with the ketone, may conveniently form the solvent for the racemisation process.
  • the ketone and the organic acid employed in the process may conveniently be used as the solvent in the racemisation reaction. Additional co-solvents may, however, also be employed.
  • racemic amino acid may be recovered by conventional methods, for example by crystallisation.
  • Processes of the present invention are normally carried out at temperatures of 60°C or more, preferably 80°C or more. Most preferred are reactions carried out under reflux. Thus where acetic acid is used as the organic acid, the reaction is carried out at 115-120°C at atmospheric pressure or at about 70°C under vacuum.
  • the advantage of the process of the present invention is to provide a racemic a-amino acid which can be subjected to resolution in order to obtain further quantities of the desired enantiomer.
  • the racemisation process is carried out in the same solution as a resolution process, so that the unwanted isomer is racemised in situ while the desired isomer is continuously removed from solution by the resolving agent.
  • the present invention provides a process for the preparation of an optically active a-amino acid, which process comprises resolving a racemic a-amino acid in the presence of a ketone and an organic acid.
  • resolving agent will depend, of course, on the particular amino acid.
  • phenylglycine may be resolved using camphor-10-sulphonic acid; 4-hydroxyphenylglycine is conveniently resolved by using diastereoisomeric salts with 3-bromocamphor-9-sulphonic acid (which is also referred to as 3-bromocamphor-8-sulphonic acid-see Japanese application No. 50-148144; Kokai 52-71440).
  • European patent application 85106310.7 discloses the resolution of 3,4 dihydroxyphenylglycine by using diastereoisomeric salts with 3-bromocamphor-9-sulphonic acid.
  • the present invention provides a process for the preparation of optically active 4-hydroxyphenylglycine or 3,4-dihydroxyphenylglycine, which process comprises allowing a 3-bromocamphor-9-sulphonate salt thereof to crystallise from a solution of a mixture of diastereoisomeric camphorsulphonate salts of a 4-hydroxyphenyglycine or 3,4 dihydroxyphenylglycine, in the presence of a ketone and an organic acid; and liberating said optically active 4-hydroxyphenylglycine or 3,4-dihydroxyphenylglycine.
  • the diastereoisomeric bromocamphorsulphonate salts are separated by preferential crystallisation.
  • the crystallisation may need to be induced by concentration of the solution, by adding a further solvent in which one diastereoisomer is less soluble, such as water; or by seed crystals of the desired diastereoisomer.
  • a further solvent in which one diastereoisomer is less soluble such as water
  • seed crystals of the desired diastereoisomer Such seeding may be particuiariy desirable for the salts of D-3,4-dihydroxyphenylglycine.
  • Suitable bases are those which are capable of liberating the 4-hydroxyphenylglycine or 3,4 dihydroxyphenylglycine from the diastereoisomeric camphor sulphonate salt or, for example, bases which are stronger than the 4-hydroxyphenylglycine or 3,4 dihydroxyphenylglycine, such as sodium acetate, potassium acetate, sodium hydroxide and potassium hydroxide.
  • This salt-splitting reaction may, surprisingly, be carried out in virtually the same solvent system as the resolution and racemisation, normally the ketone and organic acid and in particular acetic acid, thus providing a significant advantage for the process of the invention over the prior art processes.
  • the presence of a little water, for example 5-10% is desirable to prevent racemisation occurring. This water is readily removed subsequently.
  • a further advantage for the process of the invention is the resistance of ketones to degradation.
  • the process of the present invention can be operated more than 10 times in the same solvent without excessive ketone degradation.
  • the ketone may be used as the solvent for this extraction.
  • L(+)-4-hydroxyphenylglycine-3-bromocamphor-9-sulphonate (L(+)HSC) was heated at 90°C together with 0.03 g sodium acetate, 13.3 ml glacial acetic acid, and 6.6 ml methyl isobutyl ketone for 48 hours.
  • Hplc analysis showed that conversion to D(-)-4-hydroxyphenylglycine 3-bromocamphor-9-sulphonate (D(-)HSC) was in excess of 99%.
  • D(-) 3,4-dihydroxyphenylglycine bromocamphorsulphonate was prepared by adding 275 ml 2N sulphuric acid to a suspension of D(-)-3,4-dihydroxyphenylglycine (50 g) and ammonium bromocamphor-9-sulphonate (90 g) in water (100 ml). After thorough drying 9.5 g of the above salt was mixed with glacial acetic acid (100 ml), butanone (50 ml), and sodium acetate (0.3 g). The mixture was stirred and refluxed for one hour at which point it consisted of a clear orange solution.
  • Racemic 3,4-dihydroxyphenylglycine monohydrate (52 g, assay 88.47%) was added and stirred vigorously.
  • the amino acid went briefly into solution then crystallised as the bromocamphor-9-sulphonate salt. After half an hour this was filtered, washed with a minimum of glacial acetic acid and then butanone, dried and assayed. The procedure was repeated with two further additions of 20 g racemic acid.
  • the third crop appeared to be a mixture (by IR spectrum) so an equivalence point had evidently been reached.
  • a further small quantity of salt was obtained on standing at room temperature. Crops 1, 2 and 4 represent a conventional resolution with a yield of salt of about 42% (uncorrected for purity).
  • Toluene (100 ml) and sodium acetate (0.5 g) were added to the combined filtrate and washings and the solution refluxed gently with a cooled Dean and Stark head to remove a water rich lower phase.
  • Crops 1, 2, 4, 5 and 6 were suspended in 250 ml H 2 0 and treated with 50% aqueous NaOH to pH 4.5. After 1 hour stirring the product was filtered, washed with water, and dried.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Claims (8)

1. Ein Verfahren zur Racemisierung einer a-Aminosäure der Formel (I)
Figure imgb0009
in welcher R Phenyl darstellt, gegebenenfalls substituiert mit bis zu 3 Gruppen, ausgewählt aus Hydroxy oder Halogen, dadurch gekennzeichnet, daß eine optisch aktive a-Aminosäure der Formel (1), oder ein Salz derselben, mit einem Keton in Gegenwart einer organischen Säure behandelt wird.
2. Ein Verfahren wie in Anspruch 1 beansprucht, in welchem die a-Aminosäure Phenylglycin, 4-Hydroxyphenylglycin oder 3,4-Dihydroxyphenylglycin ist.
3. Ein Verfahren wie in Anspruch 1 oder 2 beansprucht, in welchem das Keton die Formel (11) hat:
Figure imgb0010
in welcher R' und R2 gleich oder verschieden sind und jeweils eine Kohlenwasserstoff- oder eine Heterocyclylgruppe bedeuten oder R' und R2 zusammen einen Cycloalkanonring vervollständigen.
4. Ein Verfahren wie in einem der vorstehenden Ansprüche beansprucht, in welchem die organische Säure eine C1-6-Alkancarbonsäure ist.
5. Ein Verfahren wie in einem der vorstehenden Ansprüche beansprucht, in welchem das Keton in einem Verhältnis von 0,5 bis 20 Mol pro Mol einer a-Aminosäure vorliegt und die organische Säure in einem Verhältnis von 5 bis 50 Mol pro Mol einer a-Aminosäure vorliegt.
6. Ein Verfahren zur Herstellung eines neuen Enantiomers einer optisch aktiven a-Aminosäure der Formel (I) oder eines Salzes derselben
Figure imgb0011
in welcher R Phenyl darstellt, gegebenenfalls substituiert mit bis zu 3 Gruppen ausgewählt aus Hydroxy oder Halogen, wobei das nicht erwünschte Enantiomer in-situ racemisiert wird, während das gewünschte Enantiomer fortlaufend aus der Lösung entfernt wird mittels eines geeigneten Trennmittels (resolving agent), dadurch gekennzeichnet, daß eine Lösung der a-Aminosäure der Formel (I) und des Trennmittels mit einem Keton und einer organischen Säure behandelt wird.
7. Ein Verfahren wie in Anspruch 6 beansprucht, in welchem die a-Aminosäure 4-Hydroxyphenylglycin oder 3,4-Dihydroxyphenylglycin ist und das Trennmittel 3-Bromcampher-9-schwefelsäure ist.
8. Ein Verfahren wie in Anspruch 6 oder 7 beansprucht zur Herstellung eines optisch aktiven 4-Hydroxyphenylglycins oder 3,4-Dihydroxyphenylglycins, welches Verfahren das Kristallisierenlassen eines 3-Bromcampher-9-schwefelsäuresalzes davon aus einer Lösung einer Mischung des diastereoisomeren Campherschwefelsäuresalzes von 4-Hydroxyphenylglycin oder 3,4-Dihydroxyphenylglycin in Gegenwart eines Ketons und einer organischen Säure und die Freisetzung des genannten optisch aktiven 4-Hydroxyphenylglycins oder 3,4-Dihydroxyphenylglycins aus diesem Salz.
EP85110569A 1984-08-30 1985-08-22 Verfahren zur Racemisierung einer alpha-Aminocarbonsäure Expired EP0173921B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT85110569T ATE34381T1 (de) 1984-08-30 1985-08-22 Verfahren zur racemisierung einer alphaaminocarbons|ure.

Applications Claiming Priority (2)

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GB8421964 1984-08-30
GB848421964A GB8421964D0 (en) 1984-08-30 1984-08-30 Chemical process

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EP0173921B1 true EP0173921B1 (de) 1988-05-18

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EP (1) EP0173921B1 (de)
JP (1) JPS6169748A (de)
AT (1) ATE34381T1 (de)
AU (1) AU4682585A (de)
DE (1) DE3562772D1 (de)
DK (1) DK391585A (de)
ES (1) ES8703827A1 (de)
GB (1) GB8421964D0 (de)
GR (1) GR852076B (de)
PT (1) PT81043B (de)
ZA (1) ZA856540B (de)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0499376A1 (de) * 1991-01-31 1992-08-19 Hoechst Celanese Corporation Asymmetrische Umwandlung von chirales Aminosäure und ihre Salze durch Fällung
DE4407197A1 (de) * 1994-03-04 1995-09-07 Hoechst Schering Agrevo Gmbh Verfahren zur Herstellung von /L/-Homoalanin-4-yl-(methyl)phosphinsäure und deren Salze durch Racematspaltung
WO1996011173A2 (en) * 1994-10-07 1996-04-18 Chiroscience Limited Racemisation of precursors to levobupivacaine and analogues thereof
US6156900A (en) * 1994-10-07 2000-12-05 Darwin Discovery Limited Racemization of precursors to levobupivacaine and analogues thereof
US6812363B2 (en) * 2002-10-15 2004-11-02 Usv Limited Racemization of optically active 2-substituted phenyl glycine esters
JP2011024572A (ja) * 2009-06-29 2011-02-10 Mitsubishi Gas Chemical Co Inc 光学活性アミノ酸の製造法
KR20170029965A (ko) * 2015-09-08 2017-03-16 주식회사 아미노로직스 D-아르기닌의 제조 방법
WO2018108794A1 (de) 2016-12-15 2018-06-21 Bayer Cropscience Aktiengesellschaft Verfahren zur herstellung von d-glufosinat oder dessen salzen unter verwendung von ephedrin
WO2018108797A1 (de) 2016-12-15 2018-06-21 Bayer Cropscience Aktiengesellschaft Verfahren zur herstellung von l-glufosinat oder dessen salzen unter verwendung von ephedrin
CA3133296A1 (en) 2019-04-16 2020-10-22 Brian Michael GREEN Methods for producing crystalline l-glufosinate ammonium monohydrate

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3458568A (en) * 1965-02-19 1969-07-29 Toa Gosei Chem Ind Process for preparing an optically inactive amino acid from an optically active amino acid
GB1417060A (en) * 1972-10-19 1975-12-10 Ajinomoto Kk Racemization of optically active n-acyl amino acids
JPS54109912A (en) * 1978-02-14 1979-08-29 Ajinomoto Co Inc Racemization of optically active amino acid ester
US4401820A (en) * 1981-01-23 1983-08-30 Tanabe Seiyaku Co., Ltd. Process for racemizing optically active α-amino acids or a salt thereof
JPS5810544A (ja) * 1981-07-09 1983-01-21 Tanabe Seiyaku Co Ltd 光学活性ｐ−ヒドロキシフエニルグリシン塩の製法

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GR852076B (de) 1985-12-23
PT81043B (en) 1987-04-06
ZA856540B (en) 1986-06-25
ES8703827A1 (es) 1987-03-01
DK391585D0 (da) 1985-08-28
DE3562772D1 (en) 1988-06-23
EP0173921A1 (de) 1986-03-12
AU4682585A (en) 1986-03-06
DK391585A (da) 1986-03-01
US4647692A (en) 1987-03-03
PT81043A (en) 1985-09-01
ATE34381T1 (de) 1988-06-15
ES546489A0 (es) 1987-03-01
JPS6169748A (ja) 1986-04-10
GB8421964D0 (en) 1984-10-03

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